Epithelial to Mesenchymal Transition in Gingival Overgrowth

Abstract

Epithelial to mesenchymal transition (EMT) occurs normally in development. In pathology, EMT drives cancer and fibrosis. Medication with phenytoin, nifedipine, and cyclosporine-A often causes gingival overgrowth. Based partly on the histopathology of gingival overgrowth, the present study investigates the hypothesis that EMT could contribute to its development. We found that phenytoin-induced human gingival overgrowth tissues, the most fibrotic drug-induced variety, contain diminished epithelial E-cadherin expression, whereas fibroblast-specific protein-1 (FSP-1) and ␣v␤6 integrin levels are up-regulated. In connective tissue stroma, fibronectin and alternatively spliced fibronectin extra type III domain A (FN-ED-A) levels are increased in overgrowth lesions. Transforming growth factor (TGF)-␤1 treatment of primary human gingival epithelial cells cultured in transwell plates resulted in inhibited barrier function as determined by reduced electrical resistance, paracellular permeability assays, and cell surface E-cadherin expression. Moreover , TGF-␤1 altered the expression of other markers of EMT determined at the mRNA and protein levels: E-cadherin decreased, whereas SLUG, fibronectin, matrix metalloproteinase (MMP)2, MMP9, and MMP13 increased. Nifedipine-and cyclosporine A-induced gingival overgrowth tissues similarly contain diminished E-cadherin and elevated levels of FSP-1 and fibronectin, but normal levels of ␣v␤6 integrin. In summary, data in vitro support that human gingival epithelial cells undergo functional and gene expression changes consistent with EMT in response to TGF-␤1, and in vivo studies show that important EMT markers occur in clinical gingival overgrowth tissues. These findings support the hypothesis that EMT likely occurs in drug-induced gingival overgrowth.

In vivo association of immunophenotyped macrophages expressing CD163 with PDGF-B in gingival overgrowth-induced by three different categories of medications

“…Spolidorio et al 24 and Nurmenniemi 25 attributed increased epithelial thickness in CsA-induced GO to the influence of connective tissue on epithelial architecture causing an increase in the mitotic activity in the oral epithelium. In addition, Sume et al 26 attributed collagenous fibrous stroma found in group II of present study to the possible association between GO and epithelial mesenchymal transition which is a process of trans-differentiation of epithelial cells into fibroblast like cells. Microscopic analysis of group III biopsies of the present study revealed a redundant fibrous tissue stroma with excessive amount of collagen and increased number of fibroblasts.…”

Loss of Basement Membrane Integrity in Human Gingival Overgrowth

“…In addition to fibrosis in the lamina propria, drug-induced gingival overgrowth is associated with thickening of epithelium and elongated rete pegs extending deep into the underlying connective tissue (Pernu et al, 1989). This phenomenon is related to expansion of the Stratum spinosum and is associated with increased mitotic activity within the epithelial layer (Ayanoglou and Lesty, 1999;Saito et al, 1999;Sume et al, 2010). It is not known, however, how such epithelial structures form and function in gingival overgrowth tissues.…”

“…It is not known, however, how such epithelial structures form and function in gingival overgrowth tissues. The underlying hypothesis of this and a previous report is that elongated rete pegs in gingival overgrowth may result from an increased level of epithelial plasticity, resulting in mesenchymal characteristics that can be considered to be a phenotypic transition known as 'epithelial to mesenchymal transition' (EMT) (Sume et al, 2010).…”

“…EMT is a process in which the phenotypic plasticity of epithelial Loss of Basement Membrane Integrity in Human Gingival Overgrowth J Dent Res 90(7) 2011 cells results in greater mesenchymal characteristics. In particular, polarity and cell-cell contacts between epithelial cells are lost, and epithelial cells become motile, migrate into connective tissue stroma, and integrate into connective tissue (Sume et al, 2010). Although additional mechanisms of fibrosis clearly exist (Krenning et al, 2010), the biological process of EMT predicts that, for epithelial cells to migrate into the connective tissue stroma, some degree of degradation of the basement membrane must occur.…”

Prevalence of Gingival Hyperplasia Secondary to Amlodipine

“…These findings provided a new additional support for the hypothesis that epithelial plasticity and epithelial to mesenchymal transition promote gingival overgrowth, resulting in compromised basal membrane structure and increased interactions between epithelial and connective tissue layers that contribute to fibrotic pathology. 19,20 Recently, Subramani et al observed that mast cells participate in many inflammatory oral diseases, particularly those associated with fibrosis. 21 They possess very diverse roles ranging from proinflammatory to immunomodulatory.…”